In melanoma, activation and suppression of specific pathways has been implicated in tumor formation, local progression, and distant metastatic spread. Therapies that target specific components of these pathways have been developed and many are currently in human trials. However, early results from the use of single agents targeting specific pathway components have been disappointing. It is now generally believed that multiple pathways, many with redundant downstream effects, are dysregulated in melanoma and therapies that target multiple pathways at once will be needed if these therapies are going to be effective. Recently, our group discovered that ectopic expression of the metabotropic glutamate receptor 1 (GRM1) is highly oncogenic when inappropriately expressed in melanocytes in vitro and in vivo. We demonstrated that targeted murine GRM1 (mGRM1) expression in melanocytes in mice is sufficient to induce spontaneous melanoma development with 100% penetrance. Furthermore, we have found that the majority of human melanoma biopsies and cell lines express the human form of GRM1 (hGRM1), suggesting that hGRM1 may be involved in the oncogenesis of many human melanomas. Indeed, genetic inactivation or pharmacological inhibition of mGRM1 expression or function suppresses melanoma cell growth, promotes apoptosis and decreases tumorigenesis in vivo. Importantly, pharmacologic depletion of the GRM1 ligand, glutamate, with the glutamate antagonist Riluzole suppresses melanoma cell growth and increases apoptosis in vitro, and promotes apoptosis and reduces melanoma tumorigenesis in vivo in mice and in humans in a preliminary trial. We therefore hypothesize that disruption of hGRM1 signaling is a novel therapeutic target for the treatment of patients with melanoma. This proposal will focus on performing a Phase I/II clinical trial of Riluzole and the multi-kinase inhibitor Sorafenib in patients with advanced stage melanoma and will integrate laboratory studies examining biologic correlates of response to this combination therapy. We will also examine the hypothesis that GRM1 signaling blockade affects signaling through the PI3K/AKT pathway with subsequent effects on downstream targets to set the groundwork for the design of future clinical trials.